Journal Article

Feeding induces cholesterol biosynthesis via the mTORC1-USP20-HMGCR axis

Shi, Xiong-Jie, Ding, Yi, Jiang, Wei, Sun, Ming, Lu, Xiao-Yi, Wang, Ju-Qiong, Hu, Ao

2020

Overview

Cholesterol is an essential lipid and its synthesis is nutritionally and energetically costly.sup.1,2. In mammals, cholesterol biosynthesis increases after feeding and is inhibited under fasting conditions.sup.3. However, the regulatory mechanisms of cholesterol biosynthesis at the fasting-feeding transition remain poorly understood. Here we show that the deubiquitylase ubiquitin-specific peptidase 20 (USP20) stabilizes HMG-CoA reductase (HMGCR), the rate-limiting enzyme in the cholesterol biosynthetic pathway, in the feeding state. The post-prandial increase in insulin and glucose concentration stimulates mTORC1 to phosphorylate USP20 at S132 and S134; USP20 is recruited to the HMGCR complex and antagonizes its degradation. The feeding-induced stabilization of HMGCR is abolished in mice with liver-specific Usp20 deletion and in USP20(S132A/S134A) knock-in mice. Genetic deletion or pharmacological inhibition of USP20 markedly decreases diet-induced body weight gain, reduces lipid levels in the serum and liver, improves insulin sensitivity and increases energy expenditure. These metabolic changes are reversed by expression of the constitutively stable HMGCR(K248R). This study reveals an unexpected regulatory axis from mTORC1 to HMGCR via USP20 phosphorylation and suggests that inhibitors of USP20 could be used to lower cholesterol levels to treat metabolic diseases including hyperlipidaemia, liver steatosis, obesity and diabetes.

• Publisher: Nature Publishing Group
• Subject: Analysis / Biosynthesis / Cholesterol / Control / Feeding methods / Physiological aspects / Proteases / Protein kinases